Omeprazole, the generic name for 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzi midazole (denoted as Formula I below) is a well-described gastric proton-pump inhibitor and is on the market as LOSEC.RTM. or PRILOSEC.RTM. for the treatment of gastric and duodenal ulcers, gastritis, duodenitis, and reflux esophagitis (see Merck Index, 12th Ed., entry 6977, and references cited therein). Omeprazole is commercially prepared via a multi-step sequence, the last step of which is oxidation of the sulfide intermediate, 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]methylthio]-1H-ben zimidazole (denoted as Formula II below), known generically as pyrmetazole, which is typically effected with a peroxy acid, such as meta-chloroperoxybenzoic acid (hereinafter referred to as MCPBA) (U.S. Pat. Nos. 4,255,431 and 5,386,032), magnesium monoperoxyphthalate (MMPP) (U.S. Pat. No. 5,391,752), or peroxyacetic acid (WO 98/09962), in a suitable non-alcoholic organic reaction solvent. The preferred oxidizing agent is usually MCPBA, and suitable non-alcoholic organic reaction solvents include aromatic hydrocarbon solvents, such as benzene and toluene, and chlorinated aliphatic hydrocarbon solvents, such as chloroform and methylene chloride, in admixture with an alcoholic solvent, such as methanol, ethanol, isopropanol, or 1-butanol. The preferred non-alcoholic organic reaction solvents are usually methylene chloride and toluene, and the preferred alcoholic solvent is ethanol.
Prior processes to omeprazole have numerous disadvantages that limit both the yield and the purity of the final product.
A significant drawback of such prior methods is incomplete oxidative conversion of pyrmetazole into omeprazole as well as non-chemoselective oxidation. Two aspects of chemoselectivity are important in the oxidation of pyrmetazole. First, pyrmetazole contains two tertiary amino groups which can compete with the sulfide group for the oxidizing agent. Although these amino groups are less reactive than the desired sulfide, they can nevertheless undergo quantitative oxidation with MCPBA below ambient temperature. Second, the product omeprazole (a sulfoxide) can also react with MCPBA to form a sulfone by-product. Non-chemoselectivity and over-oxidation, characteristic of the previous methods, arise from ineffective control over the amount of the oxidizing agent as well as the manner in which the oxidizing agent is charged into the reaction vessel. Prior methods do not use accurately determined amounts of the oxidizing agent and do not provide for careful control of its addition to the reaction mixture. Non-chemoselective, over-, and under-oxidation all contribute to high impurities and loss of yield of the final desired product.
Another disadvantage of prior procedures is the considerable loss of product in the purification and isolation steps due to solubility of omeprazole in the mother liquors and solvent washes.
A further drawback concerns diminished product quality resulting from occlusion of residual solvents and reaction by-products during the crystallization steps. It is desirable to eliminate residual levels of organic reaction solvent and recrystallization solvent impurities in the final crystalline product for toxicity/safety reasons.
It is therefore an object of the present invention to provide an improved process for the preparation, purification, and isolation of omeprazole that overcomes the yield and product purity limitations of prior methods.
It is also an object of the invention to provide compositions of omeprazole having lower levels of residual non-alcoholic organic reaction solvent after the initial crude reactive crystallization step.
It is a further object of the present invention to provide final compositions of omeprazole that contain no residual non-alcoholic organic reaction solvent within the limits of chromatographic detection and less than 20 p.p.m. of residual crystallization solvent.